Synergistic antiseptic compositions

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE EFFECT OF SYNERGISTIC MIXTURES OF 2,2&#39;&#39;-METHYLENE-BIS-(3, 4,6-TRICHLOROPHENOL)-DI-(N-METHYLCARBAMATE), TRICLOCARBAN AND HEXACHLOROPHENE.

United States Patent U.S. Cl. 252-107 6 Claims ABSTRACT OF THEDISCLOSURE Compositions possessing antibacterial activity through theeffect of synergistic mixtures of 2,2'-methylene-bis-( 3,4,6-trichlorophenol)-di-(N-methylcarbamate), triclocarban andhexachlorophene.

The present invention relates to antiseptic compositions which possesssynergistic activities through the use of a mixture of antibacterialagents. More specifically the present invention relates to a mixture oftriclocarban, hexachlorophene and a di-rnethylcarbamate,2,2'-methylenebis (3,4,6 trichlorophenol) di-(N-methylcarbamate) havingthe formula:

I l 01 Cl Antiseptic or antibacterial agents have been used in soaps andother detergent and cosmetic cleansing preparations for a considerableperiod of time. One of the most widely used types of such agent has beencertain halogenated bisphenols, such as those described in US. Pat.2,535,077, and particularly hexachlorophene[2,2-methylene-bis(3,4,6-trichlorophenol) The past decade has seen major improvements inantibacterial systems for cleaning compositions like soap, such as bythe introduction of new antibacterial agents and the introduction ofsynergistic antibacterial systems. However, the number of compounds andsystems which have been developed and are suitable from technical,safety and economic points of view has been really quite small. In orderfor a new antibacterial agent or system to become part of a successfulproduct such as a toilet soap, the compounds must possess broad spectrumantibacterial activity. Such antibacterial activity must be maintainedin the presence of soap or other cleansing agents. Chemical stability inthe presence of the cleansing composition must be maintained, as well asnon-reactivity with the other components of the cleansing compositionsuch as perfumes, antioxidants, brighteners and the like. In addition,the product must evidence mildness and safety for general use in thefinished product.

Thus relatively few antibacterial agents or bacteriostats and systemshave been found which meet all of the above requirements.

At the present time it is estimated that over 46% of all consumerdollars spent annually in the United States on toilet soap is onantibacterial and deodorant soaps. The

3,720,620 Patented Mar. 13, 1973 most important commercially usedbacteriostats for use in such cleansing compositions as soap arehexachlorophene, TCC (triclocarban), TBS(3,4,5'-tribromosalicylanjlide), and 4,4'-dichloro-3-trifluoromethylcarbanilide. While these compounds have in general excellent propertiesand are widely used, they suffer certain drawbacks. Hexachlorophene issomewhat sensitive to sunlight. The substituted ureas may be unstable inalkali media at elevated temperatures.

In efforts to play down the drawbacks of known and effectiveantibacterial agents, recent attention has been focused upon thedevelopment of synergistic bacteriostatic systems. The term synergisticactivity as applied herein means an antibacterial efiect which isgreater in combination than the sum of the antibacterial effects of theseparate components. It must be recognized that the occurrence ofsynergistic activity is highly unexpected and unusual, since the factthat a particular compound may exhibit synergism with a certain othercompound generally does not carry over to additional compounds eventhough they may have similar structures. Further synergistic activity isgenerally quite limited even as to the ratios and proportions of theindividual ingredients exhibiting synergism. An example of knownsynergism may be found in the Casely and Noel US. Pat. 3,177,155disclosing synergistic binary antibacterial systems comprising mixturesof certain isomeric trihalogenated carbanilides, particularly TCC, witha number of halogenated bisphenols and alkylated halogenated bisphenols,particularly hexachlorophene. The discovery of such synergism wasextremely important in providing soap manufacturers with the ability tonot only provide cleansing compositions having a high level ofantibacterial activity, but also to maintain such activity with agreatly reduced concentration of antibacterial agents. The latter pointis of further importance in allowing the substantial decrease of theamount of hexachlorophene employed in the antibacterial composition,thereby greatly reducing the tendency of the composition to discolorupon prolonged exposure to sunlight.

In accordance with the present invention, it has been found thatmixtures of triclocarban, hexachlorophene and 2,2 methylene bis(3,4,6trichlorophenol)-di-(N- methylcarbamate) exhibit synergisticantibacterial activity, and that this activity is maintained unimpairedwhen such mixtures are incorporated into various cleansing compositionssuch as soap and other detergent and cosmetic preparations.

It is therefore an object of the present invention to provideantibacterial compositions which include as antibacterial agents asynergistic combination of triclocarban, hexachlorophene and2,2-methylene-bis-(3,4,6-trichlorophenol di- (N-methylcarbamate It is afurther object of this invention to provide antibacterial agents whichare effective in soap and in other detergent and cosmetic mediums.

It is still another object of this invention to provide antibacterialcompositions which are effective over relatively wide ratios forproportions of the antibacterial ingredients. Other objects andadvantages and a fuller understanding of our invention will becomeapparent from the ensuing description and examples.

In a specific embodiment, our invention may be exemplified by a soapcomposition containing as the antibacterial agent a synergistic mixtureof (A) triclocarban, (B) hexachlorophene and (C)2,2'-methylenebis-(3,4,6- trichlorophenol) di (N-methylcarbamate) andwherein the ratio of A to B present in the soap in parts by weight isabout 1 to 1 and wherein the ratio of either of A or B to C in the soapin parts by weight is about 1 to 20 to about 4.8 to l. Thehexachlorophene and triclocarban may be used in the ratio of about 1-9parts by weight of the hexachlorophene to about 9-1 parts by weight oftriclocarban.

It is found that when components A, B and C of the synergistic mixtureas set forth above are used together, a germicidal effect is achievedwhich is substantially greater than the mere total of the individualeffects of the individual ingredients. Such effect is important in caseswhere it is desirable to increase the activity of the hexachloropheneingredient without employing higher concentrations. Such effect is alsoimportant in cases where it is desirable to reduce the totalconcentration of the antibacterial agents while at the same timemaintaining a desired level of antibacterial effect, or to reduce theconcentration of the hexachlorophene, thereby lowering the incidents ofdrawbacks to the use of hexachlorophene in the product while maintaininghigh antibacterial effectiveness.

The present invention is still further important in that thissynergistic phenomena occurs at the high pH conditions existing indetergent formulations such as soap.

The term soap refers to the water-soluble ammonium, phosphorus,metallic, or organic base (such as alkyl or alkoxy-alkyl containing upto about 9 carbon atoms) salts of various fatty acids or long chainsynthetic acids wherein long chain refers to aliphatic radicalscontaining from about 12 to 22 carbon atoms. Such aliphatic radicals maybe principally dodecyl, tetradecyl, hexadecyl, octadecyl; and the fattyacids may be chiefly lauric, oleic, stearic and palmetic acids. As usedin this description, the term is intended to cover all products in whichsoap is a major constituent, for example bar, flake, powder, gel andliquid soap; shaving cream; toothpaste; facial and cleansing cream; andthe like.

Further the soap ingredient may be partially, substantially orcompletely replaced with anionic type and nonionic type syntheticdetergents. The anionic type synthetics suitable for use in the presentinvention can be described as those detergents having pronouncedcleansing power and including in their molecular structure an alkylradical containing from 6 to 18 carbon atoms and a sulfonic acid orsulfuric acid ester radical. Either organic base, ammonium, sodium orpotassium salts of such anionic type detergents can be used. Principaltypes of detergents falling within this category are illustrated byalkyl-aryl sulfonates such as sodium or potassium dodecyl benzenesulfonate, sodium or potassium octadecyl benzene sulfonate, and sodiumor potassium octyl naphthalene sulfonate; the alkyl sulfates such assodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates;the sulfonated fatty acid amides such as sodium or potassium salts ofthe oleic acid amide of methyl taurine; and the sulfonatedmonoglycerides such as the mono-coconut oil fatty acid ester of sodiuml,2-hydroxypropane-3-sulfonate.

Suitable nonionic type synthetic detergents for use in the presentinvention can be described as those detergents which do not ionize insolution but owe their watersolubility to un-ionized polar groups suchas hydroxy, oxyethyl or other linkages. Principal types of detergentsfalling within this category are illustrated by the polyoxyethyleneethers of the higher fatty alcohols and alkyl phenols; the polyethyleneglycols of fatty acid; fatty alkylol amide condensation products;polymers of ethylene and propylene oxides; compounds formed by theaddition of propylene oxide to ethylene diamine followed by addition ofethylene oxide; fatty acid ethylene oxide condensation products;condensation products of ethylene oxide and a fatty acid ester of apolyhydric alcohol or sugar; and the detergents prepared by heatingtogether a higher fatty acid with a diethanolamine. Exemplary examplesof such synthetic nonionic detergents suitable for the purpose of thepresent invention are ethylene oxidetall oil fatty acid reactionproducts; isooctyl phenolethylene oxide reaction products, propyleneoxide-ethylene oxide reaction products; and combinations of isooctylphenol-ethylene oxide with coconut oil or the like fatty acid ethyleneoxide reaction products.

Relatively small amounts of the components of our synergistic mixturesare sufficient for the increased antibacterial elfects in the detergentproduct. Satisfactory results can be obtained when the combined weightsof the above three components are from 0.10% to 5.0% of the total weightof lhe detergent composition. A preferred range is a weightconcentration of about 0.21% to 4.2%, and an especially preferredproduct is one containing soap and 0.5 to 3% combined weight of theabove three components, by weight of the composition. It should beunderstood that even concentrations below the ranges set forth abovewill provide some degree of antibacterial effects, and a substantiallyhigher concentration than those referred to will also give satisfactoryresults, although there are economic and other practical considerationswhich limit the desirability of greater amounts of the antibacterialingredients in the soap or other medium.

As indicated above, the preferred ratios of the hexachlorophene to thedi-methylcarbamate is about 1 to about 4.8 parts of the hexachloropheneto about 20 to 1 parts of the di-methylcarbamate; and the preferredratio of the triclocarban to the di-methylcarbamate is about 1 to about4.8 parts of the triclocarban to about 20 to 1 parts of thedi-methylcarbamate.

The synergistic combination of the hexachlorophene, triclocarban and2,2-methylene-bis-(3,4,6-trichlorophenol)-di-(N-methylcarbamate) can beadded to the soap and other detergents by any suitable method whichresults in a uniform distribution of the agents throughout the entiremass.

Specific examples illustrating our invention are set forth as follows:

EXAMPLE I A convenient and meaningful method of measuring theantibacterial effectiveness of various agents is by means of a modifiedagar streak method utilizing a 10% soap solution (100,000 p.p.m. ofsoap) containing the various test agents. Briefly the test consists ofmaking serial dilutions of the following solution: 10 ml. of a solutioncontaining a specific quantity of the additive(s) in dimethyl formamideis dispersed into ml. of distilled water containing 10 grams of soap.All solutions are maintained at 60 C. until they are dispensed. Aliquotsof the dilutions containing concentrations of the bacteriostatic agentsranging from about 0.02 to 10 at 50 C. and thoroughly dispersed intomeasured amounts of nutrient agar. Plates are poured, allowed tosolidify, and streaked with a standard 4 mm. loopful of a 24-hour brothculture of Staphylococcus aureus FDA 209. After incubation for 24 hoursat 37 C. the bacteriostatic end point is determined. The bacteriostaticend point, hereinafter called the minimum inhibitory concentration(MIC), represents the minimum concentration in parts per million byweight of the bacteriostatic agent necessary to inhibit all growth ofthe innoculent organism. No particular minimum inhibitory concentrationhas been established to determine the usefulness of a bacteriostaticagent, although the lower the end point, the better the bacteriostaticactivity and the smaller the amount of the agent necessary to maintain aparticular degree of effectiveness. The soap utilized for theseevaluations was a neutral White toilet soap containing about 20% byweight of sodium coco soap and 80% by weight of sodium tallow soap.

Using the modifier agar streak method as set forth above it wasdetermined that a soap solution containing 1.5% of the2,2'-methylene-bis-(3,4,6-trichlorophenol)- di-(N-methylcarbamate) hadan end point or MIC of 0.20 p.p.m. It was also determined that a soapsolution containing 0.15% of hexachlorophene and 0.15% of triclocarbanhad an end point of 0.20 p.p.m. Various proportions of the abovesolutions were combined to give mixtures that would be expected to givean end point or MIC of 0.20 p.p.m., if no synergistic activity tookplace.

to about 4.821, wherein the ratio of said triclocarban to saiddi-(N-methylcarbamate) in parts by weight is about 1 to 4.8 parts of thetriclocarban to about 20 to 1 parts TAB LE Ratio of hexaehloropheneParts of 1.5% Percentage and trielo- Parts of 0.15%hexachlorodi-(N-methylhexachloro- Percentage carban to di- MIC (p.p.m.)phene and 0.15% triclocarbamate)* phone and di-(N-methyl-(N-methylversus oarban solution solution triclocarban oarbamate)*carbamate) S. aureus*2,2-mothylene-bis-(3,4,6-trichlorophenol)-di-(N-methylearbamate). No'rE.-Tested at 0.26, 0.24, 0.22, 0.18, 0.16, 0.14, 0.12, 0.10.

The results as set forth in the above table have been reproduced ingraph form on the attached drawing. In the graph the MICs (ordinate)have been plotted against the concentration (abscissa). Line Arepresents the expected MIC if the activity of the three components weremerely additive. The curved line B represents the actual MICs of acombination of the three components at the varying proportions set forthin the table. That portion of line B lying between points C and Drepresents the region in which unexpected or synergistic activity takesplace. Thus there is synergism when the ratio of the ternary mixture ofthe di-methylcarbamate to equal parts by weight of hexachlorophene andtriclocarban (parts by weight) is from about 1 to 4.8 to about 20.00 to1.

The results set forth in the foregoing examples with respect to aspecific soap (20% sodium coco and 80% sodium tallow soap) are obtainedwith soaps generally. Thus, a fatty acid soap such as sodium laurate,potassium stearate, sodium oleate, and potassium myristate will alsoproduce these results. Furthermore, the synergistic action isindependent of the soap medium and will take place in non-detergentmedia as well as in anionic detergents other than soap and in nonionicdetergent systems. At the same time, soap is a system in which thesynergistic components are highly effective and useful.

While this invention has been described and exemplitied in terms of itspreferred embodiments, those skilled in the art will appreciate thatvariations and modifications may be made without departing from thespirit and scope of the invention.

What is claimed is:

1. Antiseptic compositions consisting essentially of a detergentcomposition selected from the class consisting of water-soluble soaps,anionic synthetic detergents, and nonionic synthetic detergentscontaining a synergistic combination of triclocarban, hexachloropheneand 2,2'-methylene-bis-(3,4,6 trichlorophenol)-di-(N-methylcarbamate)wherein the ratio of said hexachlorophene to said di-(N-methylcarbamate) in parts by weight is from about 1:20

of the di-(N-methylcarbamate), and wherein the combined weights of saidtriclocarban and said hexachlorophene and said di-(N-methylcarbamate)are from about 0.10 percent to 5.0 percent of the total weight of theantiseptic compositions.

2. An antiseptic composition according to claim 1 wherein the ratio oftriclocarban to hexachlorophene is about one to one.

3. An antiseptic composition according to claim 1 wherein said detergentcomposition is a water-soluble soap.

4. An antiseptic composition according to claim 1 wherein saidcomposition is an anionic synthetic organic detergent.

5. An antiseptic composition according to claim 1 wherein said detergentcomposition is a nonionic synthetic organic detergent.

6. An antiseptic composition according to claim 1 wherein the ratio ofeach of said triclocarban and hexachlorophene to saiddi-(N-methylcarbamate) in parts by weight is from about 1:20 to about4.8: 1, and wherein the total concentration of said triclocarban,hexachlorophene and di-(N-methylcarbamate) is from about 0.1% to about5% by weight of the composition.

References Cited FOREIGN PATENTS 3/1958 Great Britain.

LEON D. ROSDOL, Primary Examiner P. E. WILLIS, Assistant Examiner US.Cl. X.R. 252-106; 424300

